Invasive Prenatal (Fetal) Diagnostic Testing

POLICY NUMBER

A.2.04.116

DESCRIPTION

Invasive prenatal (fetal) diagnostic testing may be used to identify pathogenic genetic alterations in fetuses at increased risk based on prenatal screening or in women who choose to undergo diagnostic testing due to other risk factors. This policy only addresses the use of chromosomal microarray testing, molecular diagnosis of single-gene disorders, and next-generation sequencing.

Prenatal Genetic Testing Methodologies

The focus of this policy is the use of certain invasive prenatal genetic testing methodologies in the prenatal (fetal) setting to provide a framework for evaluating the clinical utility of diagnosing monogenic disorders in this setting. The purpose of prenatal genetic testing is to identify conditions that might affect the fetus, newborn, or mother to inform pregnancy management (eg, prenatal treatment, decisions about delivery location and personnel, or pregnancy termination).

Invasive fetal diagnostic testing can include obtaining fetal tissue for karyotyping, fluorescence in situ hybridization, chromosomal microarray (CMA) testing, quantitative polymerase chain reaction (PCR), next-generation sequencing, and multiplex ligation-dependent probe amplification.

This policy only addresses the following:

• the diagnosis of copy number variants (CNVs) using CMA technology

• the diagnosis of single-gene disorders, most of which are due to single-nucleotide variants (SNVs) or very small deletions, and use molecular methods to diagnose (mainly PCR, but also multiplex ligation-dependent probe amplification)

• Next-generation sequencing.

This policy applies only if there is not a separate medical policy that outlines specific criteria for diagnostic testing. If a separate medical policy exists, then the criteria in it supersede the guidelines in this policy. This policy does NOT cover the use of:

• prenatal carrier testing ( Carrier Screening for Genetic Diseases  medical policy)

• preimplantation genetic diagnosis or screening

• noninvasive prenatal testing ( Noninvasive Prenatal Screening for Fetal Aneuploidies, Microdeletions, Single-Gene Disorders, and Twin Zygosity Using Cell-Free Fetal DNA  medical policy)

• testing in the setting of fetal demise.

Genetic disorders are generally categorized into 3 main groups: chromosomal, single gene, and multifactorial. Single-gene disorders (also known as monogenic) result from errors in a specific gene, whereas those that are chromosomal include larger aberrations that are numerical or structural.

Invasive prenatal testing refers to the direct testing of fetal tissue, typically by chorionic villus sampling or amniocentesis. Both procedures increase the risk of miscarriage. Chorionic villus sampling utilizes placental cells that are derived from the same fertilized egg as the fetus. The chorionic villi are collected for genetic evaluation under ultrasound guidance without entering the amniotic sac. During amniocentesis, a small sample of the fluid that surrounds the fetus is removed. This fluid contains cells that are shed primarily from the fetal skin, bladder, gastrointestinal tract, and amnion. Typically, CVS is done at earlier gestation than amniocentesis. Most times only one procedure is done; however, sometimes CVS has ambiguous results from maternal cell contamination or placental mosaicism such that amniocentesis might additionally be needed for clarification. Invasive prenatal procedures are usually performed in pregnancies of women who have been identified as having a fetus at increased risk for a chromosomal abnormality, or if there is a family history of a single-gene disorder. For confirming positive cell-free DNA results, amniocentesis might be preferred over CVS to avoid potential false-positive results due to confined placental mosaicism.

Chromosomal Microarray Testing

Chromosomal microarray (CMA) technology has several advantages over karyotyping, including improved resolution (detection of smaller chromosomal variants that are undetectable using standard karyotyping) and, therefore, can result in higher rates of detection of pathogenic chromosomal abnormalities. However, there are disadvantages to CMA testing, including the detection of variants of uncertain significance (VUS) and the fact that it cannot detect certain types of chromosomal abnormalities, including balanced rearrangements.

CMA analyzes abnormalities at the chromosomal level and measures gains and losses of DNA (known as copy number variants [CNVs]) throughout the genome. CMA testing detects CNVs by comparing a reference genomic sequence (“normal”) with the corresponding patient sequence. Each sample has a different fluorescent label so that they can be distinguished, and both are cohybridized to a sample of a specific reference (also normal) DNA fragment of the known genomic locus. If the patient sequence is missing part of the normal sequence (deletion) or has the normal sequence plus additional genomic material within that genomic location (eg, a duplication of the same sequence), the sequence imbalance is detected as a difference in fluorescence intensity. For this reason, standard CMA (non-SNVs, see the following) cannot detect balanced CNVs (equal exchange of material between chromosomes) or sequence inversions (the same sequence is present in reverse base-pair order) because the fluorescence intensity would not change.

CMA analysis uses thousands of cloned or synthesized DNA fragments of known genomic loci immobilized on a glass slide (microarray) to conduct thousands of comparative reactions at the same time. The prepared sample and control DNA are hybridized to the fragments on the slide, and CNVs are determined by computer analysis of the array patterns and intensities of the hybridization signals. Array resolution is limited only by the average size of the fragment used and by the chromosomal distance between loci represented by the reference DNA fragments on the slide. High-resolution oligonucleotide arrays are capable of detecting changes at a resolution of up to 50 to 100 Kb.

Types of Chromosomal Microarray Technologies

There are differences in CMA technology, most notably in the various types of microarrays. They can differ first by construction; the earliest versions used DNA fragments cloned from a bacterial artificial chromosome. They have been largely replaced by oligonucleotide (oligos; short, synthesized DNA) arrays, which offer better reproducibility. Finally, arrays that detect hundreds of thousands of SNVs across the genome have some advantages as well. An SNV is a DNA variation in which a single nucleotide in the genomic sequence is altered. This variation can occur between 2 different individuals or between paired chromosomes from the same individual and may or may not cause disease. Oligo/SNV hybrid arrays have been constructed to merge the advantages of each.

The two types of microarrays both detect CNVs, but they identify different types of genetic variation. The oligo arrays detect CNVs for relatively large deletions or duplications, including whole chromosome duplications (trisomies), but cannot detect triploidy. SNV arrays provide a genome-wide copy number analysis, and can detect consanguinity, as well as triploidy and uniparental disomy.

Microarrays may be prepared by the laboratory using the technology, or more commonly by commercial manufacturers, and sold to laboratories that must qualify and validate the product for use in their assay, in conjunction with computerized software for interpretation. The proliferation of in-house developed and commercially available platforms prompted the American College of Medical Genetics and Genomics to publish guidelines for the design and performance expectations for clinical microarrays and associated software in the postnatal setting.

At this time, no guidelines have shown whether targeted or genome-wide arrays should be used or what regions of the genome should be covered. Both targeted and genome-wide arrays search the entire genome for CNVs, however, targeted arrays are designed to cover only clinically significant areas of the genome. The American College of Medical Genetics guidelines for designing microarrays has recommended probe enrichment in clinically significant areas of the genome to maximize the detection of known abnormalities. Depending on the laboratory that develops a targeted array, it can include as many or as few microdeletions and microduplication syndromes as thought to be needed. The advantage, and purpose, of targeted arrays is to minimize the number of variants of uncertain significance (VUS).

Whole-genome CMA analysis has allowed for the characterization of several new genetic syndromes, with other potential candidates currently under study. However, whole-genome arrays also have the disadvantage of potentially high numbers of apparent false-positive results, because benign CNVs are also found in phenotypically normal populations; both benign and pathogenic CNVs are continuously cataloged and, to some extent, made available in public reference databases to aid in clinical interpretation relevance.

Clinical Relevance of Chromosomal Microarray Findings and Variants of Uncertain Significance

CNVs are generally classified as pathogenic (known to be disease-causing), benign, or a VUS.

A CNV that is considered a VUS:

• has not been previously identified in a laboratory’s patient population, or

• has not been reported in the medical literature, or

• is not found in publicly available databases, or

• does not involve any known disease-causing genes.

To determine clinical relevance (consistent association with a disease) of CNV findings, the following actions are taken:

• CNVs are confirmed by another method (eg, fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, polymerase chain reaction [PCR]).

• CNVs detected are checked against public databases and, if available, against private databases maintained by the laboratory. Known pathogenic CNVs associated with the same or similar phenotype as the patient are assumed to explain the etiology of the case; known benign CNVs are assumed to be nonpathogenic.

• A pathogenic etiology is additionally supported when a CNV includes a gene known to cause the phenotype when inactivated (microdeletion) or overexpressed (microduplication).

• The laboratory may establish a size cutoff; potentially pathogenic CNVs are likely to be larger than benign polymorphic CNVs; cutoffs for CNVs not previously reported typically range from 300 kilobases to 1 megabase.

• Parental studies are indicated when CNVs of appropriate size are detected and not found in available databases; CNVs inherited from a clinically normal parent are assumed to be benign variants whereas those appearing de novo are likely pathogenic; etiology may become more certain as other similar cases accrue.

The International Standards for Cytogenomic Arrays (ISCA) Consortium (2008) was organized; it established a public database containing de-identified whole-genome microarray data from a subset of the ISCA Consortium member clinical diagnostic laboratories. Array analysis was carried out on subjects with phenotypes including intellectual disability, autism, and developmental delay. As of July 2018, nearly 10,500 "expert reviewed" variants are listed in the ClinVar database. Data are currently hosted on ClinGen.

Use of the database includes an intralaboratory curation process, whereby laboratories are alerted to any inconsistencies among their own reported CNVs or other variants, as well as any inconsistency with the ISCA “known” pathogenic and “known” benign lists. The intralaboratory conflict rate was initially about 3% overall; following the release of the first ISCA curated track, the intralaboratory conflict rate decreased to about 1.5%. A planned interlaboratory curation process, whereby a group of experts curates reported CNVs/variants across laboratories, is currently in progress.

The consortium proposed “an evidence-based approach to guide the development of content on chromosomal microarrays and to support interpretation of clinically significant copy number variation.” The proposal defines levels of evidence (from the literature and/or ISCA and other public databases) that describe how well or how poorly detected variants or CNVs correlate with phenotype.

ISCA is also developing vendor-neutral recommendations for standards for the design, resolution, and content of cytogenomic arrays using an evidence-based process and an international panel of experts in clinical genetics, clinical laboratory genetics, genomics, and bioinformatics.

Single-Gene (Mendelian) Disorders

Single-gene (Mendelian) disorders include those with an inheritance mode of autosomal dominant or recessive, X-linked dominant or recessive. Women may be identified as being at increased risk for having a fetus with an inherited genetic condition because of previously affected pregnancies, a family history in a suggestive pattern of inheritance, or being a member of a subpopulation with elevated frequencies of certain autosomal recessive conditions.

Most Mendelian disorders are caused by SNVs or very small deletions or duplications. Monogenic variants are diagnosed by molecular methods, mainly PCR for SNVs, but also other methods like multiplex ligation-dependent probe amplification for very small deletions and duplications. Approximately 5,000 known disorders are inherited in this fashion. Diagnostic tests are currently available for most of the common monogenic disorders, as well as for a number of the more rare disorders. For most single-gene disorders, testing in the prenatal setting requires knowledge of the familial variants.

Next-Generation Sequencing

Next-generation sequencing (NGS) has been used to identify pathogenic variants in disease-associated genes in many Mendelian disorders. Approximately 85% of known disease-causing variants occur within 1% of the genome that encodes for proteins (exome). Therefore, whole-exome sequencing can cost-effectively capture the majority of protein-coding regions. However, concerns remain about technical complexity, coverage, bioinformatics, interpretation, variants of uncertain significance, as well as ethical issues.

Commercially Available Tests

Many academic and commercial laboratories offer CMA testing and single-gene disorder testing. Many laboratories also offer reflex testing, which may be performed with microarray testing added if karyotyping is normal or unable to be performed (due to no growth of cells). The test should be cleared or approved by the FDA, or performed in a Clinical Laboratory Improvement Amendment (CLIA)–certified laboratory.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer LDTs must be licensed by the CLIA for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of this test.

Related medical policies -

• Genetic Testing for Developmental Delay/Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies

• Whole Exome and Whole Genome Sequencing for Diagnosis of Genetic Disorders

• Carrier Screening for Genetic Diseases

• Fetal Surgery for Prenatally Diagnosed Malformations

• First-Trimester Detection of Down Syndrome Using Fetal Ultrasound Markers Combined with Maternal Serum Assessment

• Noninvasive Prenatal Screening for Fetal Aneuploidies, Microdeletions, Single-Gene Disorders, and Twin Zygosity Using Cell-Free Fetal DNA

POLICY

Chromosomal Microarray Testing

In individuals who are undergoing invasive diagnostic prenatal (fetal) testing, chromosome microarray (CMA) testing may be considered medically necessary as an alternative to karyotyping (see Policy Guidelines).

Single-Gene Disorders

Invasive diagnostic prenatal (fetal) testing for molecular analysis for single-gene disorders may be considered medically necessary when a pregnancy has been identified as being at high risk:

1. For autosomal dominant conditions, at least one of the parents has a known pathogenic variant.

2. For autosomal recessive conditions:

   • Both parents are suspected to be carriers or are known to be carriers, OR

   • One parent is clinically affected and the other parent is suspected to be or is a known carrier.

3. For X-linked conditions: A parent is suspected to be or is a known carrier.

AND, ALL of the following are met:

1. The natural history of the disease is well understood, and there is a reasonable likelihood that the disease is one with high morbidity in the homozygous or compound heterozygous state, AND

2. Any variants have high penetrance, AND

3. The genetic test has adequate sensitivity and specificity to guide clinical decision making and residual risk is understood, AND

4. An association of the marker with the disorder has been established.

If the above criteria for molecular analysis of single-gene disorders are not met, invasive diagnostic prenatal (fetal) testing is considered investigational.

Next-Generation Sequencing

The use of next-generation sequencing in the setting of invasive prenatal testing is considered investigational.

POLICY EXCEPTIONS

None 

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Fetal Malformations

Fetal malformations identified by ultrasound, characterized as major or minor malformations, whether isolated or multiple, may be part of a genetic syndrome, despite a normal fetal karyotype.

Major malformations are structural defects that have a significant effect on function or social acceptability. They may be lethal or associated with possible survival with severe or moderate immediate or long-term morbidity. Examples by organ system include: genitourinary: renal agenesis (unilateral or bilateral), hypoplastic/cystic kidney; cardiovascular: complex heart malformations; musculoskeletal: osteochondrodysplasia/osteogenesis imperfecta, clubfoot, craniosynostosis; central nervous system: anencephaly, hydrocephalus, myelomeningocele; facial clefts; body wall: omphalocele/gastroschisis; and respiratory: cystic adenomatoid lung malformation.

Single-Gene Disorders

An individual may be suspected of being a carrier if there is a family history of or ethnic predilection for a disease. Carrier screening is not recommended if the carrier rate is less than 1% in the general population.

In most cases, before a prenatal diagnosis using molecular genetic testing can be offered, the familial variant must be identified, either in an affected relative or carrier parent(s). Therefore, panel testing in this setting would not be considered appropriate.

In some cases, the father may not be available for testing, and the risk assessment to the fetus will need to be estimated without knowing the father’s genetic status.

Genetics Nomenclature Update

The Human Genome Variation Society (HGVS) nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 1). The Society's nomenclature is recommended by the Human Variome Project, the HUman Genome Organization (HUGO), and the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.

Table 1. Nomenclature to Report on Variants Found in DNA

Table 2. ACMG-AMP Standards and Guidelines for Variant Classification

Genetic Counseling

Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting. 

POLICY HISTORY

04/09/2015: Approved by Medical Policy Advisory Committee.

08/28/2015: Medical policy revised to add ICD-10 codes.

11/20/2015: Policy description updated regarding single-gene disorders. Policy statements unchanged.

06/07/2016: Policy number A.2.04.116 added.

06/27/2017: Policy description updated regarding the purpose of prenatal genetic testing and laboratory testing. "Mutation" changed to "variant" throughout policy. Policy Guidelines updated regarding indications for CMA testing, standard terminology for variant classification, and genetic counseling. Code Reference section updated to revise code description for CPT code 81405, effective 07/01/2017.

12/22/2017: Code Reference section updated to revise description for CPT code 81405 effective 01/01/2018.

08/21/2018: Policy description and policy section updated to change "chromosomal microarray analysis" to "chromosomal microarray testing." Policy statements unchanged. Policy Guidelines updated regarding genetics nomenclature and genetic counseling.

09/10/2019: Policy reviewed; no changes.

09/09/2020: Policy reviewed; no changes.

12/15/2021: Updated related medical policies in Policy Description. Policy statements unchanged. Policy Guidelines updated to remove information regarding CMA testing. Changed "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity." Code Reference section updated to revise code description for CPT codes 81228 and 81229, effective 01/01/2022.

09/08/2022: Policy description updated regarding chorionic villus sampling and amniocentesis. Policy statement updated to change "patients" to "individuals." Policy Guidelines updated regarding genetic counseling.

09/11/2023: Policy reviewed. Medical policy links updated. Policy statements unchanged.

09/11/2024: Policy reviewed; no changes.

09/16/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross and Blue Shield Association Policy # 2.04.116

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

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